Herpes simplex virus (HSV) infections in humans result in sporadic but recurrent lesions that appear at the site of the initial infection, and are now known to be the result of the reactivation of latent virus that resides within sensory neurons. As a large percentage of the human population experience some form of HSV infection, this virus represents a significant health issue. In this application, we propose a series of experiments that will investigate the cellular mechanisms that control the reactivation of latent HSV in sensory neurons. Based on prior studies of the response of peripheral neurons to axotomy, and the finding that the axotomy of sensory neurons triggers HSV reactivation, we hypothesize that a combination of neurotrophin withdrawal and cytokine secretion triggers HSV reactivation. To test this hypothesis and to identify intracellular signaling mechanisms that control HSV reactivation, we propose the following aims: 1. To characterize the sensory neurons that support ESV reactivation from latency by examining the expression of neurotrophin and cytokine receptors in latently infected neurons that are induced to support HSV reactivation. 2. To use neurotrophins, cytokines, and specific blockers of these factors to examine whether neurotrophins and cytokines regulate HSV latency and reactivation. 3. To identify the intracellular signaling pathways that are activated by extracellular stimuli that induce HSV reactivation in latently infected neurons, and to determine if these specific pathways play a critical role in regulating HSV latency and reactivation. Taken together, these aims will provide new insight into the cellular mechanisms that control the reactivation of latent HSV and may allow the generation of new therapeutics that could help to inhibit the reactivation process.